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.2008 Feb;36(2):570-7.
doi: 10.1093/nar/gkm1057. Epub 2007 Dec 1.

Nepsilon-formylation of lysine is a widespread post-translational modification of nuclear proteins occurring at residues involved in regulation of chromatin function

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Nepsilon-formylation of lysine is a widespread post-translational modification of nuclear proteins occurring at residues involved in regulation of chromatin function

Jacek R Wisniewski et al. Nucleic Acids Res.2008 Feb.

Abstract

Post-translational modification of histones and other chromosomal proteins regulates chromatin conformation and gene activity. Methylation and acetylation of lysyl residues are among the most frequently described modifications in these proteins. Whereas these modifications have been studied in detail, very little is known about a recently discovered chemical modification, the N(epsilon)-lysine formylation, in histones and other nuclear proteins. Here we mapped, for the first time, the sites of lysine formylation in histones and several other nuclear proteins. We found that core and linker histones are formylated at multiple lysyl residues located both in the tails and globular domains of histones. In core histones, formylation was found at lysyl residues known to be involved in organization of nucleosomal particles that are frequently acetylated and methylated. In linker histones and high mobility group proteins, multiple formylation sites were mapped to residues with important role in DNA binding. N(epsilon)-lysine formylation in chromosomal proteins is relatively abundant, suggesting that it may interfere with epigenetic mechanisms governing chromatin function, which could lead to deregulation of the cell and disease.

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Figures

Figure 1.
Figure 1.
(A) Acetylated, dimethylated and formylated lysyl residues show similar structures. (B) Complete mass separation of the otherwise identical dimethylated and formylated peptides. Boxplot of mass deviations from theoretical masses for formylation and dimethylation in histone H3 measured using the LTQ-Orbitrap instrument. The box represents the interquartile range of 25–75%, the center line represents median, and ‘whiskers’ (small horizontal lines) extend to the most extreme ratio up to 1.5-fold interquartile range. The mass differences of dimethylated or formylated peptides are 28.0313 and 27.9949 Da, respectively, versus unmodified peptide. Mass deviations for dimethylation are taken from Supplementary Table S2.
Figure 2.
Figure 2.
The MS/MS fragmentation spectra of (A)EIAQDFfKTDLR formylated and (B)EIAQDFdmKTDLR dimethylated peptides of Histone H3. The major groups of ions produced on cleavage of peptide bonds by low energy collision fragmentation areb ions extending from the N-terminus of a peptide, andy ions extending from its C-terminal part. The comprehensive introduction to the peptide sequencing by mass spectrometry is given by Steen and Mann (33).
Figure 3.
Figure 3.
High accuracy MS/MS spectra of peptides dimethylated (A,C,E) and formylated (B,D,F) at the same residue, respectively. (A andB) Modifications at K-108 in histone H2B. (C andD) Modifications at K-43 in histone H2B. (E andF) Modifications at K-77 in histone H4. In contrast to dimethylation, formylation was observed mainly on peptides that were not cut at the modified lysyl residue. An example of the MS and MS/MS data interpretation: after the MS scan, theESYSVYVYKVLK peptide (B) was identified as carrying an extra mass of 27.995 Da that corresponds to the delta mass of formylation. Peptide fragmentation analysis reveals that, starting fromy4 ion (KVLK), the formyl group is added toy-ion series. The observations, additionally supported by the presence ofb10 (ESYSVYVYKV) andb11 (ESYSVYVYKVL) ions with the mass shift indicative of formylation, unambiguously position the modification at the middle lysyl residue—ESYSVYVYfKVLK. Average absolute mass accuracy of all assigned peaks was better than 2 p.p.m.
Figure 4.
Figure 4.
Dimethylated (dm) and formylated (f) forms of the peptide LLLPGELA*K (from histone H2B; K-108) resolved by chromatography. Inserts show the mass envelopes of dimethylated and formylated peptides.
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